Project Summary/Abstract Heart failure after a myocardial infarction is primarily due to death of cardiomyocytes, suggesting that successful cell-based therapies will replace cardiomyocytes to restore heart function. To that end, this proposal focuses on generating large human cardiac grafts using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in engineered cardiac tissue with biomaterial delivery of therapeutic growth factors and small molecule drugs. We have developed scaffold-free engineered cardiac tissue with hiPSC- cardiomyocytes and the extracellular matrix that they secrete. These cardiac tissue patches are implanted on the epicardial surface of infarcted hearts, but integration with the host is minimal and improved cardiac function is absent. Therefore, this proposal aims to improve host vascularization of the graft (Aim 1), survival and proliferation of hiPSC-derived cardiomyocytes (Aim 2), and force generation by hiPSC-cardiomyocytes (Aim 3). In Aim 1, we will develop biodegradable alginate microspheres loaded with the angiogenic proteins vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). These will be optimized in vitro and in vivo for controlled protein release and incorporated into cardiac patches for implantation in the infarcted rat heart. In Aim 2, we will use alginate microspheres loaded with insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG-1), and Y27632 (a small molecule inhibitor of Rho-associated kinase) to improve hiPSC- cardiomyocyte survival and proliferation during cardiac patch formation and after implantation. In Aim 3, we use chemical, electrical, and mechanical conditioning to promote hiPSC-cardiomyocyte hypertrophy and contractile strength. The current proposal aims to address deficiencies in cell-based cardiac therapy and is innovative in its approach, using degradable biomaterials for therapeutic protein/drug delivery within engineered cardiac tissue. These immediate research goals will encourage my development as an independent investigator. During the mentored K99 phase, I will learn to fabricate alginate microspheres loaded with proteins and drugs. Integrating controlled-release systems with cardiac tissue engineering will result in a unique niche for my research career. It is my long-term career goal to establish an interdisciplinary cardiovascular bioengineering lab that approaches biological and medical problems with novel technologies in tissue engineering, biomaterials, physiology, biophysics, and stem cell biology.